Oral dosage forms, such as tablets and capsules, of pharmaceuticals are widely used dosage forms. However, certain patients are unable to tolerate oral dosage forms due to their inability to swallow the tablet or capsule, due to age, infirmity, or lack of consciousness. Thus, it would be desirable to be able to administer the pharmaceutical via a parenteral route, such as intravenous, intramuscular, or subcutaneous injection. Formulating solid pharmaceuticals for administration via parenteral routes can be problematic, however, because of the frequent difficulty of solubilizing the solid active ingredient in a pharmaceutically acceptable liquid solvent.
The low solubility problem has been addressed in the following ways:    1. Solubilizing surfactants may be used to increase the solubility of the active ingredient in the solvent. Unfortunately, the solubilizing surfactants may cause anaphylactic reactions in susceptible patients.    2. Oil-in-water emulsions may be used but such formulations suffer from a number of drawbacks, including pain at the injection site, poor physical stability, potential for embolisms, and the need for strict aseptic handling.    3. Complexing the active ingredients with amphipathic agents that increase their solubility (such as β-cyclodextrin) may be used, but these suffer limitations including higher cost and their currently limited acceptance by regulatory agencies for use in human pharmaceutical products.
[[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]acetic acid dihydrate (USAN name alvimopan) and its active metabolite are peripherally-acting μ opioid antagonists that may be used in the treatment of postoperative ileus, postpartum ileus, pruritis, constipation, opioid bowel dysfunction, urinary retention, biliary spasm, opioid bowel dysfunction, colic, postoperative nausea, and/or postoperative vomiting as well as other indications. Alvimopan is currently available in solid dosage form. However, it would be desirable to provide the active ingredient in an injectable form to avoid the problems with swallowing tablets or capsules or in administering to patients who are undergoing surgery and not conscious. Alvimopan and its active metabolite are 3,4-disubstituted-4-aryl piperidines that are zwitterions. They have extremely low solubility in water and many common pharmaceutically acceptable solvents.
What would be desirable are injectable dosage formulations of alvimopan and related 4-aryl substituted piperidine compounds that are zwitterionic in nature. The present invention is directed to these and other important objectives.